Cheung Lydia W T, Au Simon C L, Cheung Annie N Y, Ngan Hextan Y S, Tombran-Tink Joyce, Auersperg Nelly, Wong Alice S T
Department of Zoology, University of Hong Kong, 4S-14 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong.
Endocrinology. 2006 Sep;147(9):4179-91. doi: 10.1210/en.2006-0168. Epub 2006 Jun 15.
Epithelial ovarian carcinoma is the most lethal gynecological cancer. However, little is known about the molecular mechanisms underlying the disease development and progression. In this study, we found that the expression of pigment epithelium-derived factor (PEDF) was greatly reduced in ovarian tumors and in ovarian cancer cell lines when compared with their normal precursor, ovarian surface epithelium (OSE). In addition, we showed that exogenous PEDF inhibited the growth of cultured human OSE as well as ovarian cancer cell lines, whereas targeted inhibition of endogenous PEDF using small interfering RNA or neutralizing PEDF antibody promoted the growth of these cells, confirming that the growth-inhibitory effect was PEDF specific. We also report for the first time that estrogen is an important upstream regulator of PEDF in human OSE. Treatment of the cultured cells with 17 beta-estradiol (E2) inhibited the expression of PEDF protein and mRNA in a dose- and time-dependent manner, which could be reversed by the specific estrogen receptor antagonist, ICI 182,780, indicating that the regulation was estrogen receptor-mediated. We further showed that this down-regulation of PEDF gene transcription was a direct, primary effect of E2. E2 promoted OSE and ovarian cancer cell growth, whereas simultaneous treatment with E2 and PEDF abrogated the estrogenic growth stimulation of these cells. This study is the first to demonstrate a role of PEDF in OSE biology and ovarian cancer and suggests that the loss of PEDF may e of relevance in carcinogenesis.
上皮性卵巢癌是最致命的妇科癌症。然而，对于该疾病发生发展的分子机制却知之甚少。在本研究中，我们发现与正常前体卵巢表面上皮（OSE）相比，色素上皮衍生因子（PEDF）在卵巢肿瘤及卵巢癌细胞系中的表达大幅降低。此外，我们发现外源性PEDF可抑制培养的人OSE及卵巢癌细胞系的生长，而使用小干扰RNA靶向抑制内源性PEDF或用中和性PEDF抗体则可促进这些细胞的生长，这证实了生长抑制作用具有PEDF特异性。我们还首次报道雌激素是人类OSE中PEDF的重要上游调节因子。用17β-雌二醇（E2）处理培养细胞可剂量和时间依赖性地抑制PEDF蛋白和mRNA的表达，而这种抑制作用可被特异性雌激素受体拮抗剂ICI 182,780逆转，表明该调节是由雌激素受体介导的。我们进一步表明，PEDF基因转录的这种下调是E2的直接主要作用。E2可促进OSE和卵巢癌细胞生长，而E2与PEDF同时处理则可消除这些细胞的雌激素生长刺激作用。本研究首次证明了PEDF在OSE生物学及卵巢癌中的作用，并提示PEDF的缺失可能与致癌作用相关。
